The present invention relates to a method for producing α-hydroxycarboxylic acid and optically active α-hydroxycarboxylic acid, both of which are useful as a pharmaceutical intermediate or the like.
As a method for producing α-hydroxycarboxylic acid, hydrolysis of cyanohydrin is known. Such hydrolysis is generally carried out in an aqueous solvent containing cyanohydrin and an acid catalyst (e.g. concentrated hydrochloric acid), after hydrolysis, the reaction solution is a single solution.
However, for the above hydrolysis reaction, there are some problems in that the reaction solution becomes dark brown due to the generation of a colored substance, or the removal of by-products is difficult, resulting in the difficulty of obtaining of a good yield of high purity α-hydroxycarboxylic acid.
Furthermore, optically active α-hydroxycarboxylic acid have previously been produced by a method, which comprises: obtaining optically active cyanohydrin by the asymmetric addition of hydrogen cyanide to a corresponding carbonyl compound in an organic solvent such as an alcoholic solvent, an ester solvent, an ethereal solvent, a carboxylic solvent and a hydrocarbon-based solvent, in the presence of enzymes such as (S)-hydroxynitrilelyase and (R)-hydroxynitrilelyase extracted from plants or enzymes produced by a gene recombinant microorganism, into which a gene of those enzymes is incorporated; and hydrolyzing the obtained optically active cyanohydrin (e.g. Synthesis, July 1990, 575-578; Tetrahedron Letters, 32, 2605-2608 (1991); Japanese Patent Application filed Nos. 63-219388 and 5-317065; WO98/30711).
In these methods, hydrolysis is performed after the isolation of optically active cyanohydrin, or in consideration of efficiency, hydrolysis is performed without the removal of the reaction solvent used in the production process of the optically active cyanohydrin.
The known methods for synthesizing optically active α-hydroxycarboxylic acid by hydrolysis of optically active cyanohydrin include, for example, a method described in Synthesis, July 1990, 575-578 and a method described in Tetrahedron Letters, 32, 2605-2608 (1991), wherein reaction with concentrated hydrochloric acid at room temperature is followed by reaction at reflux temperature.
With regard to these methods, however, since a large amount of hydrochloric acid, about 30 times the amount of cyanohydrin by molar ratio is used, industrial application of these methods involves many disadvantages such as the high-cost raw materials, low productivity related to the necessity of a huge reactor, a large amount of waste liquid and so on. Furthermore, for the reason that generally α-hydroxycarboxylic acid of interest is highly soluble in water, in a case where, after reaction with a large amount of acid, the substance is purified by operations such as extraction or crystallization, a large amount of substance may disadvantageously remain in aqueous solution, having low yield.
Still more, where inappropriate reaction conditions are applied to a reaction, a side reaction or racemization reaction may often occur, resulting in a low yield and low optical purity of α-hydroxycarboxylic acid.